Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes

Graubert, Timothy A.; Shen, Dong; Li, Ding; Okeyo-Owuor, Theresa; Lunn, Cara L; Shao, Jin; Krysiak, Kilannin; Harris, Christopher; Koboldt, Daniel C.; Larson, David E.; McLellan, Michael D.; Dooling, David J.; Abbott, Rachel M.; Fulton, Robert S.; Schmidt, Heather; Kalicki-Veizer, Joelle; O’Laughlin, Michelle; Grillot, Marcus; Baty, Jack; Heath, Sharon E.; Frater, John L.; Nasim, Talat; Link, Daniel C.; Tomasson, Michael H.; Westervelt, Peter; DiPersio, John F.; Mardis, Elaine R.; Ley, Timothy J.; Wilson, Richard K.; Walter, Matthew J.

doi:10.1038/ng.1031

Cited by 518 publications

(558 citation statements)

References 47 publications

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“…To confirm that somatic gene mutations prime HSPCs for pyroptosis in MDSs, we performed comparative analyses of published gene expression profiles from human and murine SRSF2 (GSE65349) and U2AF1 mutants (GSE30195 and GSE66793) vs WT, TET2 knockout (GSE27816), and primary MDS (GSE19429) vs normal HSPCs and found uniform upregulation of pyroptosis effectors, consistent with transcriptional priming. [39][40][41][42][43] Importantly, in MDS BM specimens, BM plasma concentration of S100A9 positively correlated with NLRP3 MFI, percentage and MFI of plasma ASC specks, and the presence of SGMs and variant allele frequency (supplemental Figure 8). Furthermore, both the percentage and MFI of plasma ASC specks were significantly increased in MDS patients harboring SGMs (supplemental Figure 8D-E).…”

Section: Org Frommentioning

confidence: 91%

The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype

Basiorka¹,

McGraw²,

Eksioglu³

et al. 2016

Blood

282

350

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Key Points• Key biological features of MDSs are explained by NLRP3 inflammasome activation, which drives pyroptotic cell death and b-catenin activation.• Alarmin signals and founder gene mutations license this redox-sensitive inflammasome platform.Despite genetic heterogeneity, myelodysplastic syndromes (MDSs) share features of cytological dysplasia and ineffective hematopoiesis. We report that a hallmark of MDSs is activation of the NLRP3 inflammasome, which drives clonal expansion and pyroptotic cell death. Independent of genotype, MDS hematopoietic stem and progenitor cells (HSPCs) overexpress inflammasome proteins and manifest activated NLRP3 complexes that direct activation of caspase-1, generation of interleukin-1b (IL-1b) and IL-18, and pyroptotic cell death. Mechanistically, pyroptosis is triggered by the alarmin S100A9 that is found in excess in MDS HSPCs and bone marrow plasma. Further, like somatic gene mutations, S100A9-induced signaling activates NADPH oxidase (NOX), increasing levels of reactive oxygen species (ROS) that initiate cation influx, cell swelling, and b-catenin activation. Notably, knockdown of NLRP3 or caspase-1, neutralization of S100A9, and pharmacologic inhibition of NLRP3 or NOX suppress pyroptosis, ROS generation, and nuclear b-catenin in MDSs and are sufficient to restore effective hematopoiesis. Thus, alarmins and founder gene mutations in MDSs license a common redox-sensitive inflammasome circuit, which suggests new avenues for therapeutic intervention. (Blood. 2016;128(25):2960-2975

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Section: Org Frommentioning

confidence: 91%

The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype

Basiorka¹,

McGraw²,

Eksioglu³

et al. 2016

Blood

282

350

View full text Add to dashboard Cite

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“…PRPF6 is essential for splicing of a small subset of genes in colon cancer Recent studies have described mutations in spliceosomal components and suggest an emerging role for splicing regulation in human disease (Ebert and Bernard 2011;Wang et al 2011;Yoshida et al 2011;Graubert et al 2012 ;Hahn and Scott 2012;Imielinski et al 2012;Quesada et al 2012). A mutation in PRPF6 (PRPF6 R729W ) in its C-terminal tetraco-peptide repeat (TPR) domain has been reported to impair tri-snRNP assembly and function and lead to a heritable form of RP (Tanackovic et al 2011).…”

Section: Integrative Analysis Of Colon Cancer Identified Prpf6 As a Rmentioning

confidence: 99%

“…One example is the tri-snRNP (small ribonucleoprotein) complex, which consists of U4/U5/U6 proteins and is known to cause an autosomal dominant form of retinitis pigmentosa (adRP) when mutated (Sharp 1988;Tanackovic et al 2011;Will and Lü hrmann 2011). More recently, recurrent somatic mutations have been identified in a number of spliceosome components in cancers (Ebert and Bernard 2011;Wang et al 2011;Yoshida et al 2011;Graubert et al 2012;Hahn and Scott 2012;Imielinski et al 2012;Quesada et al 2012), raising speculation that the spliceosome may play a role in tumor growth. Nevertheless, the molecular bases and consequences of spliceosome dysregulation in cancer development are not yet known.…”

mentioning

confidence: 99%

An integrative analysis of colon cancer identifies an essential function for PRPF6 in tumor growth

Adler¹,

McCleland²,

Yee

et al. 2014

Genes Dev.

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The spliceosome machinery is composed of multimeric protein complexes that generate a diverse repertoire of mRNA through coordinated splicing of heteronuclear RNAs. While somatic mutations in spliceosome components have been discovered in several cancer types, the molecular bases and consequences of spliceosome aberrations in cancer are poorly understood. Here we report for the first time that PRPF6, a member of the trisnRNP (small ribonucleoprotein) spliceosome complex, drives cancer proliferation by preferential splicing of genes associated with growth regulation. Inhibition of PRPF6 and other tri-snRNP complex proteins, but not other snRNP spliceosome complexes, selectively abrogated growth in cancer cells with high tri-snRNP levels. Highresolution transcriptome analyses revealed that reduced PRPF6 alters the constitutive and alternative splicing of a discrete number of genes, including an oncogenic isoform of the ZAK kinase. These findings implicate an essential role for PRPF6 in cancer via splicing of distinct growth-related gene products.

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“…4,6,26 OTHER SPLICEOSOME MUTATIONS In MDS, eight genes encoding proteins involved in RNA splicing are mutated with a variable frequency. [1][2][3] In addition to SF3B1, U2AF35 and SRSF2 are among the most frequently mutated in MDS and may be associated with prognosis and phenotype. [27][28][29] SRSF2 is also frequently mutated in leukemic transformation of myeloproliferative neoplasm.…”

Section: Sf3b1 Mutationsmentioning

confidence: 99%

“…[1][2][3] The results have included identification of approximately 10 acquired mutations per patient sample and confirmation of the frequency of previously recognized mutations. 1 More importantly, the particular studies revealed the existence of mutations in genes whose products are involved in controlling the mechanism of splicing of pre-messenger RNA.…”

Section: Introductionmentioning

confidence: 99%

Spliceosome and other novel mutations in chronic lymphocytic leukemia and myeloid malignancies

et al. 2012

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Spliceosome mutations represent a new generation of acquired genetic alterations that affect both myeloid and lymphoid malignancies. A substantial proportion of patients with myelodysplastic syndromes (MDSs) or chronic lymphocytic leukemia (CLL) harbor such mutations, which are often missense in type. Genotype-phenotype associations have been demonstrated for one of these mutations, SF3B1, with ring sideroblasts in MDS and 11q22 deletions in CLL. Spliceosome mutations might result in defective spliceosome assembly, deregulated global mRNA splicing, nuclear-cytoplasm export and altered expression of multiple genes. Such mutations are infrequent in other lymphomas, which instead display a separate group of novel mutations involving genes whose products are believed to affect histone acetylation and methylation and chromatin structure (for example, EZH2 and MLL2). On the other hand, some mutations (for example, NOTCH1) occur in both CLL and other immature and mature lymphoid malignancies. In the current review, we discuss potential mechanisms of cell transformation associated with spliceosome mutations, touch upon the increasing evidence regarding the clonal involvement of hematopoietic stem cells in some cases of otherwise mature lymphoid disorders and summarize recent information on recently described mutations in lymphomas. Leukemia (2012Leukemia ( ) 26, 2027Leukemia ( -2031 doi:10.1038/leu.2012 Keywords: CLL; MDS; mutations; spliceosome INTRODUCTIONIn a series of recently published work, the coding sequences of the DNA obtained from mononuclear cells of the bone marrow of patients with myelodysplastic syndromes (MDSs) were compared with presumably germline DNA (T lymphocytes or buccal swab). [1][2][3] The results have included identification of approximately 10 acquired mutations per patient sample and confirmation of the frequency of previously recognized mutations. 1 More importantly, the particular studies revealed the existence of mutations in genes whose products are involved in controlling the mechanism of splicing of pre-messenger RNA. Such mutations were mutually exclusive and were detected in 45-85% of patients with MDS; 1 the majority constituted missense mutations located in restricted regions of proteins.A similar analysis was conducted in chronic lymphocytic leukemia (CLL) where DNA from tumor cells (CD19 þ and CD5 þ lymphocytes) was compared with that of non-tumor cells (granulocytes or fibroblasts). [4][5][6][7] In addition to genes already known to be mutated in this disease, such as TP53 and ATM, 11 genes were found to be recurrently affected. 4,6 The pathway analyses predicted that these mutations affected DNA damage repair and cell cycle, the Wnt, NOTCH1 and inflammatory/TLR signaling pathways, and, as was the case in MDS, control of splicing mechanisms. 4 The common novel observation, from the above-mentioned studies, in both MDS and CLL, was the identification of mutations in genes whose products are involved in the control of RNA splicing. 8 The involvement of oncogenes in RNA processing h...

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Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes

Cited by 518 publications

References 47 publications

The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype

The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype

An integrative analysis of colon cancer identifies an essential function for PRPF6 in tumor growth

Spliceosome and other novel mutations in chronic lymphocytic leukemia and myeloid malignancies

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